The Clinical Genetics Branch (CGB) integrates molecular and clinical observations in cancer genetics into an interdisciplinary approach involving epidemiologic, clinical, genetic, behavioral, statistical and laboratory methods to define the role of susceptibility genes in cancer etiology. The primary research goal: translate recent advances in molecular genetics into evidence-based management strategies for persons at increased genetic risk of cancer. The central research strategy: detailed and meticulous assessment of the individual members of cancer-prone families. Hereditary Breast/Ovarian Cancer Hereditary breast and ovarian cancer (HBOC) is a long-standing DCEG research interest. Family members come to the Clinical Center for genetic risk assessment, counseling, genetic testing and results disclosure (Protocol 02-C-0212). 172 prospective follow-up, 35 with deleterious mutations in BRCA1 or BRCA2, and 2 which segregate the CHEK2 variant, 1100delC. We reported that this rare allele doubles the risk of developing breast cancer in the general population, and likely accounts for a small fraction of BRCA1/2-negative hereditary breast/ovarian cancer families. Thirty-one BRCA mutation-carrying families have been under active follow-up from 5 to 35 years; in this cohort, the prospective risks of breast, ovarian, fallopian tube and peritoneal cancers are being quantified. These families were offered risk-reducing surgery long before BRCA1/2 had been cloned. Our first report identified a 62% decrease in the risk of breast cancer among women who had undergone prophylactic oophorectomy. Two additional manuscripts are under review: (1) quantification of the absolute & relative risks of selected cancers; and (2) description of a novel statistical technique for estimating cumulative cancer risk, accounting for competing risks and delayed cohort entry. Our BRCA mutation-negative families comprise a resource for evaluating new candidate high-penetrance breast cancer susceptibility genes. Two such genes (ZBRK1 and BRIP1), did not contribute to the risk of breast and ovarian cancer in these families. DNA from these families is being pooled in an international study of genetic modifiers of BRCA1/2 penetrance. This cohort of mutation-positive families was used in reports which refuted prior claims that (a) BRCA1 carriers have a lower ratio of male offspring than do BRCA2 carriers, and (b) the AIB1 polyglutamine repeat modifed the risk of BRCA-related breast cancer. We continue to expand our collection of DNA samples from persons known to be either positive or negative for BRCA1/2 mutations, to facilitate studies of genetic modifiers of gene expression. We have added 170 mutation-positive families recruited to our Breast Imaging Study, and samples from 2249 participants in GOG-199, the National Ovarian Cancer Prevention and Early Detection Study. Two additional manuscripts based on biological samples derived from HBOC cohort members are under review, one evaluating linkage disequilibrium around the BRCA1 locus in Ashkenazi Jews, and the other evaluating BRCA1 mRNA expression in culture lymphocytes as a possible test to distinguish carriers from non-carriers. Our study of BRCA1/2 founder mutations in a series of 1000 Ashkenazi Israelis with prostate cancer during documented a two-fold excess of prostate cancer among mutation carriers, supporting the hypothesis that prostate cancer is part of the spectrum of BRCA-related cancers. No differences in age at diagnosis or in histopathology between mutation-related and -unrelated cases were identified. In these same families, we have developed psychosocial/behavioral research protocols to address issues related to breast cancer screening, early diagnosis, behavioral, educational and psychosocial dynamics related to the process of genetic risk assessment and testing. We reported the ethical issues that arise when a family member lied to relatives about their own genetic test results.